Functional studies on the Wilson copper P-type ATPase and toxic milk mousemutant

The Wilson protein (WND; ATP7B) is an essential component of copper homeost asis. Mutations in the ATP7B gene result in Wilson disease, which is charac terised by hepatotoxicity and neurological disturbances. In this paper, we provide the first direct biochemical evidence that the WND protein function s as a copper-translocating P-type ATPase in mammalian cells. Importantly, we have shown that the mutation of the conserved Met1386 to Val, in the Atp 7B for the mouse model of Wilson disease, toxic milk (tx), caused a loss of Cu-translocating activity. These investigations provide strong evidence th at the toxic milk mouse is a valid model for Wilson disease and demonstrate a link between the loss of catalytic function of WND and the Wilson diseas e phenotype. (C) 2001 Academic Press.